Amyloid-Beta Interaction with Metals in Alzheimer’s Disease Jennifer ChenDrexel University Department of ChemistryDrexel University, Philadelphia, PA 19104Submitted: December 8, 2012
Abstract Alzheimer’s disease (AD) is the most common form of dementia among elderly people. There has been a lot of research done on the disease. Studies have shown that a protein called amyloid-beta (Aβ) has a large role in Alzheimer’s disease. The amyloid-beta protein is a protein that interacts with transition metals in synaptic transmission. In an Alzheimer’s brain, there is a high concentration of transition metals that causes the amyloid-beta to dysfunction. This then leads to the formation of amyloid plaques and neuronal loss. In this paper, the mechanisms and process are explained about the amyloid-beta protein and it interactions with transition metals.
Outline I. Introduction II. What are the causes of Alzheimer’s Disease III. What is amyloid- beta and what does it interact with? IV. What is the role of trace metals in the brain? V. Normal mechanism of amyloid-beta with copper, zinc, and iron in the brain VI. Mechanism of amyloid-beta with copper, zinc, and iron in Alzheimer’s Disease VII. Therapeutics for Alzheimer’s Disease Oxidative Stress a. Antioxidants b. Chelators
Introduction Alzheimer’s disease is the most common form of dementia among elderly people. About 14.5 million elderly are said to have Alzheimer’s disease [1]. It is a brain disorder that impairs a person’s ability to go about daily functions. Alzheimer’s impairs the parts of the brain that controls memory, thought processing and communications. The disease begins affecting the brain after the age of 60 and increase as age increases. The disease was first discovered in 1905 by Dr. Alois Alzheimer [2]. He was a German doctor who had a female patient that died of an unknown mental disease. The physical appearance of the patient’s brain showed reduction in size of the frontal and temporal lobes which are regions of the brain that are involved in learning and memory processes. He noticed that her brain tissue contained clumps which are now known as amyloid-beta plaques [1]. These plaques are now known as a biomarker of Alzheimer's disease. In addition, scientists have also found out that these plaques cause nerve cells to die and caused by chemical imbalances in the brain. These chemical imbalances impairs brain signal that are involved in memory.
What are the causes of Alzheimer’s Disease? There is no one real known cause for Alzheimer’s disease. There are a few hypotheses that have been proposed for the cause of the disease. The most popular hypothesis is the amyloid hypothesis where there is an over-production of amyloid-beta (Aβ) due to location of the gene for the amyloid precursor protein (APP) on chromosome 21 [3]. Through the over-expression of Aβ produces toxic plaque that causes neuron cell death. Another hypothesis is the cholinergic hypothesis. This hypothesis postulates that AD is caused by the reduced synthesis of acetylcholine, a neurotransmitter important for memory and learning functions [3,4]. Other hypotheses are based on dietary and age effects. There have been studies that have linked cardiovascular factors to the development of AD. This is due to the fact that cholesterol affects the thickness and fluidity of the cell membrane where a critical cleavage step of Aβ occurs. Therefore depending of the cell membrane it influences the site of cleavage [3]. In many other age-related diseases, oxidative stress and changes in energy metabolism play a pivotal role on how they progress. Free radicals are produced during metabolism and can cause damages to proteins, lipids and nucleic acids which may cause mutation that may allow the higher levels of Aβ [5,6,7]. In this paper will discuss more about how abnormal concentration of trace metals can affect the production of amyloid-beta plaques.
What is amyloid- beta and what does it interact with? Amyloid- beta is a peptide that is produced through the cleavage of the amyloid precursor protein (APP). Aβ is found in normal brain and is responsible for the activation of some enzymes, protection against oxidative stress, regulation of cholesterol transport, and anti-inflammatory activity of the brain. These proteins interact with metal ions zinc, copper, and iron involved in synaptic transmission. However, as a person ages, there is an increase in copper and iron in the brain which causes oxidation of amyloid-beta. The oxidation of these proteins causes misfolding of the protein and leads to the deposits in the brain. The deposits cause synaptic and neuronal loss in the brain. Many scientists believe that the accumulation of the protein is the main factor of the mechanism of Alzheimer’s disease.
What is the role of metals in the brain? Another important component of brain activity is metals. Some metals that are found in the brain are copper, zinc, and iron. All these metals all have some role in brain activity and in Alzheimer’s disease. Iron is one of the most important metals in the brain [8]. It is used to carry oxygen to the brain and used in the formation of free radicals with oxygen. A disturbance of the levels of iron in the brain indicates a neurodegenerative disorder because there is lack of oxygen carried to the brain. Copper and zinc ions are found on enzymes and are then released in the synapse transmission [8]. These metals are essential to these enzymes because they have oxidation and reduction properties which provide the ability to transfer electrons to the enzymes. If the redox chemistry is not regulated properly, reactive oxygen species (ROS) can be produced and can cause damage to proteins, lipids and nucleic acids. In healthy individuals the levels of these trace metals are highly regulated. With normal aging metal regulation mechanisms become perturbed which leads to abnormal metal-dependent enzyme function, mitochondrial dysfunctions and increase levels of reactive oxygen species.
Normal mechanism of amyloid-beta with copper, zinc, and iron
Figure 1: Mechanism of normal amyloid-beta interaction with copper, zinc, and iron [9]
Figure 1 shows the mechanism of normal amyloid-beta interaction with copper, zinc, and iron. In normal brain function, when metal such as copper, zinc and iron are present in low concentrations, the amyloid-beta proteins are produced by the type-II iron-responsive element (IRE-II). The IRE-II produces more amyloid-beta through translation of the of amyloid precursor proteins. Once amyloid-beta are produced, it binds copper and iron that will be transported to the plasma and it binds to zinc released by the synapse and brought into the cortical cell. The concentrations of these metals are found to be low in normal human brains. However in an Alzheimer’s brain the concentrations of these metals increase. In normal function, amyloid-beta is responsible for component of cellular metal-ion metabolism and the efflux of copper and iron.
Mechanism of amyloid-beta with copper, zinc, and iron in Alzheimer’s Disease
Figure 2: Mechanism of amyloid-beta interaction with copper, zinc, and iron in Alzheimer’s disease [9]
As a person ages, the amount of copper and iron increases which leads to the over production of amyloid-beta needed to regulate the metal levels. It regulates copper and iron by binding it and transporting it to the plasma membrane. Figure 2 shows the mechanism of amyloid-beta interaction with copper, zinc, and iron in Alzheimer’s disease. As the metal levels increase it causes hypermetallation of the amyloid-beta protein. Some of the hypermetallated protein is catalyzed to produce hydrogen peroxide from the oxygen in the body. Hypermetallation of the amyloid-beta protein occurs when amyloid-beta catalyzes the reduction of Cu2+ to Cu+ and Fe3+ to Fe2+ and when the metals are reduced it then reacts with molecular oxygen. The product that is made is hydrogen peroxide. When there are not enough of enzymes to catalyze the hydrogen peroxides, the peroxide will then react with the reduced metal. The resulting product of this reaction is toxic hydroxyl radicals. Hydrogen peroxide can also react with the oxygen and give the same hydroxyl radical [6]. In addition, the copper amyloid complex can also reacts with hydrogen peroxide to produce cross-linked forms of the protein. The zinc metal that is released from the synapse transmission is also link to the complexes forming a large cross-linked complex. This large complex is what is not as aggregate amyloid plaques. The hydrogen peroxide enters into the cell and reacts with copper and iron ions inside the cell and produces hydroxyl radicals and oxidized nucleic acids, proteins, and lipids [9].
Basic mechanism that causes oxidative stress In biological reactions, most reactive oxygen species (ROS) are formed by a redox reaction between molecule oxygen and transition metals like copper and iron. Normally, once oxygen reacts with one of the metals, there are usually enzymes present and are ready to utilize the ROS products. However, when the reaction is not regulated by enzymes there and ROS will form in the presence of hydrogen peroxide. These radicals will then cause an increase in free carbonyls and peroxidation of lipids. These radicals have a longer half life which in turns allows them to leave their site of origin and find its way into other parts of the body. In our body there are many polyunsaturated fatty acids which are easily oxidizable and these radicals can easily react with these fatty acids. As a conclusion of the results the free radicals causes lipid peroxidation, which leads to abnormal cell function of the cell membrane and cell death [7].
Consequence of the oxidation-reduction property that is involved in Alzheimer’s Disease The brain is an active organ that requires high metabolism. The brain is 2% of body mass, but it consumes about 20% of the oxygen entered into the body. Therefore regulating oxidative balance is very important for proper function of the brain. In Alzheimer’s patients, it is found that there is an abnormal oxidative metabolism in the brain, which leads scientists to believe there is a link between oxidative stress and Alzheimer’s disease [10]. A consequence of the redox property of the metal is it can be very toxic to cells when there is an imbalance of the metals. When there is too many of these metals it causes cellular oxidative damage by generating high levels of hydroxyl radicals. When there is a lack of these transition metals it also harmful to the cells. When there is a deficiency, it causes a decrease in the amount of metal dependent enzymes that are critical in maintaining cellular oxidative homeostasis. The disruption of copper and iron in molecular processes gives evidence for increase in oxidative damage to lipids, nucleic acids, and proteins. In an Alzheimer’s brain the concentration of copper and iron increases compared to a normal brain [7,10,11,12]. The metals are accumulated in the brain and cause plaques to form when the metal react with amyloid [7,10,11,12].
Metal ions interact with the amyloid-beta protein extracellularly and intracellularly. In early studies, scientists believed the accumulation of extracellular, insoluble amyloid-beta in the brain was the main process of the disease. However in later research, scientist found that the soluble intermediate amyloid-beta were more toxic. Therefore to the theory that the amyloid plaques was not the main cause of the dysfunction of the brain. Instead the amyloid plaques are the conclusion of the more critical process of the disease. For normal function of amyloid-beta in synaptic transmission a very small concentration of metals is needed. Therefore, scientists had concluded that the amount of metal concentration within the brain is the critical factor of irregular function of the amyloid-beta protein [13,14].
Therapeutics for Alzheimer’s Disease Oxidative Stress
Antioxidants There have been some therapeutic inventions developed to help to slow down the oxidation reaction of amyloid-beta and metals. One therapeutic is antioxidants; they have promising evidence that can slow down Alzheimer’s by slowing down the damage done by oxidative stresses. There are potential benefits of vitamin supplements working as prophylactics for Alzheimer’s. There have been studies done on vitamin E and vitamin C and have found they have benefits for elderly [15]. Gorrypin has found to a molecule that looks for radicals and protect cells from oxidative stress. Another antioxidant is melatonin which protect against amyloid-beta toxicity and it also showed improvement in brain functions. Gingko biloba extract is an antioxidant that has neuroprotective properties and helps improve neural functions of Alzheimer patients. Antioxidants are not a cure for Alzheimer’s disease, even though it may improve or slow the process of Alzheimer’s disease.
Chealtors Another way to slow down the lipid oxidation process is to attack the generation of free radicals. To slow the process of the generation of free radicals is by adding a complex to the mechanism which will attach to the reduced metal ion and prevent it from reducing again to produce the hydroxyl radical. Even though this will be a breakthrough for Alzheimer’s, it is still in the process of being researched. The main property for these complexes to accomplish is to be able to go through the blood brain barrier. The blood- brain barrier is a membrane structure made of tightly packed endothelial cells that protects the brain from chemicals found in blood. The barrier blocks molecules except for lipid soluble molecules such as oxygen and steroid hormones. These molecules also can also be transport systems like sugars. Molecules that are greater than 500 Daltons cannot cross through the barrier. In addition, the blood brain barriers are also surrounded by Glial cells that produce myelin which is about 80% lipid fat and 20% proteins. As a conclusion since it is surrounded by hydrophobic molecules, it will make it hard for hydrophilic molecules to get through [5,16]. This one property eliminated a large amount of these metal binding complexes called metal chelators [5]. Some compounds that are potential therapeutics treatments for Alzheimer’s disease are bicyclam analogue JKL169 (1,1’-xyly bis- 1,4,8,11 tetraazacyclotetradecane), clioquinol, desferrioamine, triene and tricyclodecan-9 yl-xanthogenate [7].
Studies of bicyclam analogue JKL169 (1,1’-xyly bis- 1,4,8,11 tetraazacyclotetradecane) in rats showed that it is successful at reducing copper levels in the brain. The copper levels in the blood of rats were normal [7]. Desferrioamine is a chealtor for iron but can also bind to copper, zinc and aluminum. There is not enough studies that has been done to show true evidence that the compound can reduce oxidative stress. Another downfall of this compound is it cannot be taken orally. Triene (triethylenetetramine) is used to treat Wilson’s disease. Wilson’s disease is hereditary disease where there is an accumulation of copper in body tissue and causes liver disease. When the compound was tested against Alzheimer’s, there was no reduction of amyloid plaques in the brain, this may be the caused by not being able to cross over the blood brain barrier [7]. Tricyclodecan-9 yl-xanthogenate is another chealtor that can be used to reduce oxidative stress. There was a study done showed that when amyloid-beta was exposed to tricyclodecan-9 yl-xanthogenate there was a decrease in oxidative stress [7].
Another chealtor that has been studied is clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) [17,18]. Clinoquinol shows real promising results in reducing oxidative stress. This compound was an antibiotic in the 1970’s and was taken off the market in 1971. It was taken off the market because at the time they believed a side effect was the development of subacute myelo-optico-neuropathy (SMON), which is a virus that causes the muscles to weaken and not function properly [19]. Later found out that the compound was not linked to SMON because 25% of the people did not take the antibiotic had SMON [19]. The reason that was concluded was due to the lack of vitamin B-12 consumed by the population. When the compound was tested on mice with high levels of amyloid-beta protein, the amount of amyloid proteins found in the rats decreased 49%. The compound is able to cross through the blood brain barrier and in addition the levels of copper and zinc decreased in the mice[20]. This concludes that the complexes are formed and are not being reduced. The compound is now in clinical trial phase II [18]. The patients being tested showed positive results and the patients had no sign of SMON while taking clinoquinol [16,19].
Conclusion In conclusion, metals play an important role in Alzheimer’s disease. When a person ages the amount of transition metals are not as regulated. This deregulation of the metal concentrations leads to dysfunction of the important protein, amyloid-beta in the brain. When scientist figured out that biological metals could be a cause of Alzheimer’s, scientists were able to test existing chealtors and synthesize new chealtors that can decrease the metal levels. This will lead to a possible cure, prevention in the future for Alzheimer’s disease. The potential therapeutics looks promising for the disease.
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Jennifer ChenDrexel University Department of ChemistryDrexel University, Philadelphia, PA 19104Submitted: December 8, 2012
Abstract
Alzheimer’s disease (AD) is the most common form of dementia among elderly people. There has been a lot of research done on the disease. Studies have shown that a protein called amyloid-beta (Aβ) has a large role in Alzheimer’s disease. The amyloid-beta protein is a protein that interacts with transition metals in synaptic transmission. In an Alzheimer’s brain, there is a high concentration of transition metals that causes the amyloid-beta to dysfunction. This then leads to the formation of amyloid plaques and neuronal loss. In this paper, the mechanisms and process are explained about the amyloid-beta protein and it interactions with transition metals.
Outline
I. Introduction
II. What are the causes of Alzheimer’s Disease
III. What is amyloid- beta and what does it interact with?
IV. What is the role of trace metals in the brain?
V. Normal mechanism of amyloid-beta with copper, zinc, and iron in the brain
VI. Mechanism of amyloid-beta with copper, zinc, and iron in Alzheimer’s Disease
VII. Therapeutics for Alzheimer’s Disease Oxidative Stress
a. Antioxidants
b. Chelators
Introduction
Alzheimer’s disease is the most common form of dementia among elderly people. About 14.5 million elderly are said to have Alzheimer’s disease [1]. It is a brain disorder that impairs a person’s ability to go about daily functions. Alzheimer’s impairs the parts of the brain that controls memory, thought processing and communications. The disease begins affecting the brain after the age of 60 and increase as age increases. The disease was first discovered in 1905 by Dr. Alois Alzheimer [2]. He was a German doctor who had a female patient that died of an unknown mental disease. The physical appearance of the patient’s brain showed reduction in size of the frontal and temporal lobes which are regions of the brain that are involved in learning and memory processes. He noticed that her brain tissue contained clumps which are now known as amyloid-beta plaques [1]. These plaques are now known as a biomarker of Alzheimer's disease. In addition, scientists have also found out that these plaques cause nerve cells to die and caused by chemical imbalances in the brain. These chemical imbalances impairs brain signal that are involved in memory.
What are the causes of Alzheimer’s Disease?
There is no one real known cause for Alzheimer’s disease. There are a few hypotheses that have been proposed for the cause of the disease. The most popular hypothesis is the amyloid hypothesis where there is an over-production of amyloid-beta (Aβ) due to location of the gene for the amyloid precursor protein (APP) on chromosome 21 [3]. Through the over-expression of Aβ produces toxic plaque that causes neuron cell death. Another hypothesis is the cholinergic hypothesis. This hypothesis postulates that AD is caused by the reduced synthesis of acetylcholine, a neurotransmitter important for memory and learning functions [3,4]. Other hypotheses are based on dietary and age effects. There have been studies that have linked cardiovascular factors to the development of AD. This is due to the fact that cholesterol affects the thickness and fluidity of the cell membrane where a critical cleavage step of Aβ occurs. Therefore depending of the cell membrane it influences the site of cleavage [3]. In many other age-related diseases, oxidative stress and changes in energy metabolism play a pivotal role on how they progress. Free radicals are produced during metabolism and can cause damages to proteins, lipids and nucleic acids which may cause mutation that may allow the higher levels of Aβ [5,6,7]. In this paper will discuss more about how abnormal concentration of trace metals can affect the production of amyloid-beta plaques.
What is amyloid- beta and what does it interact with?
Amyloid- beta is a peptide that is produced through the cleavage of the amyloid precursor protein (APP). Aβ is found in normal brain and is responsible for the activation of some enzymes, protection against oxidative stress, regulation of cholesterol transport, and anti-inflammatory activity of the brain. These proteins interact with metal ions zinc, copper, and iron involved in synaptic transmission. However, as a person ages, there is an increase in copper and iron in the brain which causes oxidation of amyloid-beta. The oxidation of these proteins causes misfolding of the protein and leads to the deposits in the brain. The deposits cause synaptic and neuronal loss in the brain. Many scientists believe that the accumulation of the protein is the main factor of the mechanism of Alzheimer’s disease.
What is the role of metals in the brain?
Another important component of brain activity is metals. Some metals that are found in the brain are copper, zinc, and iron. All these metals all have some role in brain activity and in Alzheimer’s disease. Iron is one of the most important metals in the brain [8]. It is used to carry oxygen to the brain and used in the formation of free radicals with oxygen. A disturbance of the levels of iron in the brain indicates a neurodegenerative disorder because there is lack of oxygen carried to the brain. Copper and zinc ions are found on enzymes and are then released in the synapse transmission [8]. These metals are essential to these enzymes because they have oxidation and reduction properties which provide the ability to transfer electrons to the enzymes. If the redox chemistry is not regulated properly, reactive oxygen species (ROS) can be produced and can cause damage to proteins, lipids and nucleic acids. In healthy individuals the levels of these trace metals are highly regulated. With normal aging metal regulation mechanisms become perturbed which leads to abnormal metal-dependent enzyme function, mitochondrial dysfunctions and increase levels of reactive oxygen species.
Normal mechanism of amyloid-beta with copper, zinc, and iron
Figure 1: Mechanism of normal amyloid-beta interaction with copper, zinc, and iron [9]
Figure 1 shows the mechanism of normal amyloid-beta interaction with copper, zinc, and iron. In normal brain function, when metal such as copper, zinc and iron are present in low concentrations, the amyloid-beta proteins are produced by the type-II iron-responsive element (IRE-II). The IRE-II produces more amyloid-beta through translation of the of amyloid precursor proteins. Once amyloid-beta are produced, it binds copper and iron that will be transported to the plasma and it binds to zinc released by the synapse and brought into the cortical cell. The concentrations of these metals are found to be low in normal human brains. However in an Alzheimer’s brain the concentrations of these metals increase. In normal function, amyloid-beta is responsible for component of cellular metal-ion metabolism and the efflux of copper and iron.
Mechanism of amyloid-beta with copper, zinc, and iron in Alzheimer’s Disease
Figure 2: Mechanism of amyloid-beta interaction with copper, zinc, and iron in Alzheimer’s disease [9]
As a person ages, the amount of copper and iron increases which leads to the over production of amyloid-beta needed to regulate the metal levels. It regulates copper and iron by binding it and transporting it to the plasma membrane. Figure 2 shows the mechanism of amyloid-beta interaction with copper, zinc, and iron in Alzheimer’s disease. As the metal levels increase it causes hypermetallation of the amyloid-beta protein. Some of the hypermetallated protein is catalyzed to produce hydrogen peroxide from the oxygen in the body. Hypermetallation of the amyloid-beta protein occurs when amyloid-beta catalyzes the reduction of Cu2+ to Cu+ and Fe3+ to Fe2+ and when the metals are reduced it then reacts with molecular oxygen. The product that is made is hydrogen peroxide. When there are not enough of enzymes to catalyze the hydrogen peroxides, the peroxide will then react with the reduced metal. The resulting product of this reaction is toxic hydroxyl radicals. Hydrogen peroxide can also react with the oxygen and give the same hydroxyl radical [6]. In addition, the copper amyloid complex can also reacts with hydrogen peroxide to produce cross-linked forms of the protein. The zinc metal that is released from the synapse transmission is also link to the complexes forming a large cross-linked complex. This large complex is what is not as aggregate amyloid plaques. The hydrogen peroxide enters into the cell and reacts with copper and iron ions inside the cell and produces hydroxyl radicals and oxidized nucleic acids, proteins, and lipids [9].
Basic mechanism that causes oxidative stress
In biological reactions, most reactive oxygen species (ROS) are formed by a redox reaction between molecule oxygen and transition metals like copper and iron. Normally, once oxygen reacts with one of the metals, there are usually enzymes present and are ready to utilize the ROS products. However, when the reaction is not regulated by enzymes there and ROS will form in the presence of hydrogen peroxide. These radicals will then cause an increase in free carbonyls and peroxidation of lipids. These radicals have a longer half life which in turns allows them to leave their site of origin and find its way into other parts of the body. In our body there are many polyunsaturated fatty acids which are easily oxidizable and these radicals can easily react with these fatty acids. As a conclusion of the results the free radicals causes lipid peroxidation, which leads to abnormal cell function of the cell membrane and cell death [7].
Consequence of the oxidation-reduction property that is involved in Alzheimer’s Disease
The brain is an active organ that requires high metabolism. The brain is 2% of body mass, but it consumes about 20% of the oxygen entered into the body. Therefore regulating oxidative balance is very important for proper function of the brain. In Alzheimer’s patients, it is found that there is an abnormal oxidative metabolism in the brain, which leads scientists to believe there is a link between oxidative stress and Alzheimer’s disease [10]. A consequence of the redox property of the metal is it can be very toxic to cells when there is an imbalance of the metals. When there is too many of these metals it causes cellular oxidative damage by generating high levels of hydroxyl radicals. When there is a lack of these transition metals it also harmful to the cells. When there is a deficiency, it causes a decrease in the amount of metal dependent enzymes that are critical in maintaining cellular oxidative homeostasis. The disruption of copper and iron in molecular processes gives evidence for increase in oxidative damage to lipids, nucleic acids, and proteins. In an Alzheimer’s brain the concentration of copper and iron increases compared to a normal brain [7,10,11,12]. The metals are accumulated in the brain and cause plaques to form when the metal react with amyloid [7,10,11,12].
Metal ions interact with the amyloid-beta protein extracellularly and intracellularly. In early studies, scientists believed the accumulation of extracellular, insoluble amyloid-beta in the brain was the main process of the disease. However in later research, scientist found that the soluble intermediate amyloid-beta were more toxic. Therefore to the theory that the amyloid plaques was not the main cause of the dysfunction of the brain. Instead the amyloid plaques are the conclusion of the more critical process of the disease. For normal function of amyloid-beta in synaptic transmission a very small concentration of metals is needed. Therefore, scientists had concluded that the amount of metal concentration within the brain is the critical factor of irregular function of the amyloid-beta protein [13,14].
Therapeutics for Alzheimer’s Disease Oxidative Stress
Antioxidants
There have been some therapeutic inventions developed to help to slow down the oxidation reaction of amyloid-beta and metals. One therapeutic is antioxidants; they have promising evidence that can slow down Alzheimer’s by slowing down the damage done by oxidative stresses. There are potential benefits of vitamin supplements working as prophylactics for Alzheimer’s. There have been studies done on vitamin E and vitamin C and have found they have benefits for elderly [15]. Gorrypin has found to a molecule that looks for radicals and protect cells from oxidative stress. Another antioxidant is melatonin which protect against amyloid-beta toxicity and it also showed improvement in brain functions. Gingko biloba extract is an antioxidant that has neuroprotective properties and helps improve neural functions of Alzheimer patients. Antioxidants are not a cure for Alzheimer’s disease, even though it may improve or slow the process of Alzheimer’s disease.
Chealtors
Another way to slow down the lipid oxidation process is to attack the generation of free radicals. To slow the process of the generation of free radicals is by adding a complex to the mechanism which will attach to the reduced metal ion and prevent it from reducing again to produce the hydroxyl radical. Even though this will be a breakthrough for Alzheimer’s, it is still in the process of being researched. The main property for these complexes to accomplish is to be able to go through the blood brain barrier. The blood- brain barrier is a membrane structure made of tightly packed endothelial cells that protects the brain from chemicals found in blood. The barrier blocks molecules except for lipid soluble molecules such as oxygen and steroid hormones. These molecules also can also be transport systems like sugars. Molecules that are greater than 500 Daltons cannot cross through the barrier. In addition, the blood brain barriers are also surrounded by Glial cells that produce myelin which is about 80% lipid fat and 20% proteins. As a conclusion since it is surrounded by hydrophobic molecules, it will make it hard for hydrophilic molecules to get through [5,16]. This one property eliminated a large amount of these metal binding complexes called metal chelators [5]. Some compounds that are potential therapeutics treatments for Alzheimer’s disease are bicyclam analogue JKL169 (1,1’-xyly bis- 1,4,8,11 tetraazacyclotetradecane), clioquinol, desferrioamine, triene and tricyclodecan-9 yl-xanthogenate [7].
Studies of bicyclam analogue JKL169 (1,1’-xyly bis- 1,4,8,11 tetraazacyclotetradecane) in rats showed that it is successful at reducing copper levels in the brain. The copper levels in the blood of rats were normal [7]. Desferrioamine is a chealtor for iron but can also bind to copper, zinc and aluminum. There is not enough studies that has been done to show true evidence that the compound can reduce oxidative stress. Another downfall of this compound is it cannot be taken orally. Triene (triethylenetetramine) is used to treat Wilson’s disease. Wilson’s disease is hereditary disease where there is an accumulation of copper in body tissue and causes liver disease. When the compound was tested against Alzheimer’s, there was no reduction of amyloid plaques in the brain, this may be the caused by not being able to cross over the blood brain barrier [7]. Tricyclodecan-9 yl-xanthogenate is another chealtor that can be used to reduce oxidative stress. There was a study done showed that when amyloid-beta was exposed to tricyclodecan-9 yl-xanthogenate there was a decrease in oxidative stress [7].
Another chealtor that has been studied is clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) [17,18]. Clinoquinol shows real promising results in reducing oxidative stress. This compound was an antibiotic in the 1970’s and was taken off the market in 1971. It was taken off the market because at the time they believed a side effect was the development of subacute myelo-optico-neuropathy (SMON), which is a virus that causes the muscles to weaken and not function properly [19]. Later found out that the compound was not linked to SMON because 25% of the people did not take the antibiotic had SMON [19]. The reason that was concluded was due to the lack of vitamin B-12 consumed by the population. When the compound was tested on mice with high levels of amyloid-beta protein, the amount of amyloid proteins found in the rats decreased 49%. The compound is able to cross through the blood brain barrier and in addition the levels of copper and zinc decreased in the mice[20]. This concludes that the complexes are formed and are not being reduced. The compound is now in clinical trial phase II [18]. The patients being tested showed positive results and the patients had no sign of SMON while taking clinoquinol [16,19].
Conclusion
In conclusion, metals play an important role in Alzheimer’s disease. When a person ages the amount of transition metals are not as regulated. This deregulation of the metal concentrations leads to dysfunction of the important protein, amyloid-beta in the brain. When scientist figured out that biological metals could be a cause of Alzheimer’s, scientists were able to test existing chealtors and synthesize new chealtors that can decrease the metal levels. This will lead to a possible cure, prevention in the future for Alzheimer’s disease. The potential therapeutics looks promising for the disease.
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